Macroinitiator containing hydrophobic segment

ABSTRACT

The present invention relates to macroinitiators comprising at least one hydrophobic segments in a molecule, wherein a molecular weight of the hydrophobic segment is 300 to 1800. The present invention further relates to block copolymers, wetting agent and polymeric materials having the block copolymers of the present invention associated with, which is suitable for medical devices, particularly for ophthalmic devices, including contact lenses, ophthalmic lenses, punctal plugs and artificial corneas.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/482,260, filed on May 4, 2011 entitled MACROINITIATOR CONTAININGHYDROPHOBIC SEGMENT, the contents of which are incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to macroinitiators useful for formingblock copolymers. The present invention further relates to blockcopolymers, wetting agents and polymeric materials, as well as, medicaldevices incorporating the polymeric materials having the blockcopolymers of the present invention.

DESCRIPTION OF THE RELATED ART

Various compounds have been disclosed as suitable for treating preformedsilicone hydrogel contact lenses including surface active segmentedblock copolymers, substantially water-soluble silicone-containingsurfactants, functionalized hybrid PDMS/polar amphipathic copolymerblock systems, including polydimethylsiloxane-PVP block copolymers and(meth)acrylated polyvinylpyrrolidone. WO2006/039467 discloses a blockcopolymer obtained by polymerizing a hydrophilic monomer using ahydrophobic macro azoinitiator, including VPS 0501 and VPS 1001 siloxanecontaining macro azoinitiators of which the siloxane units havemolecular weights of 5,000 and 10,000. WO2006/039467 discloses that theblock copolymers disclosed therein may be incorporated into the reactionmixtures and polymerized therewith to form medical devices havingimproved characteristics, including wettability.

WO2008/112874 similarly discloses that a block copolymer obtained bypolymerizing a hydrophilic monomer using a hydrophobic macroazoinitiator can be used as a lens care component for contact lenses. Nodetails are provided relating to the size of the macro azoinitiator orthe process for making same. No properties are provided for thesolution.

However, large polysiloxane segments can be difficult to solubilize inaqueous solutions, such as contact lens packaging, cleaning and caresolutions. This can result in cloudy solutions which do not impart thedesired improvement in wettability to the articles being treated. Thusthere remains a need for methods for improving the properties of contactlenses and particularly silicone hydrogel contact lenses.

SUMMARY OF THE INVENTION

The present invention relates to macroinitiators comprising at least onehydrophobic segment in a molecule, wherein the molecular weight of thehydrophobic segments is 300 to 1800.

DETAILED DESCRIPTION OF THE INVENTION

As used herein “non-reactive” means incapable of forming significantcovalent bonding. The absence of significant covalent bonding means thatwhile a minor degree of covalent bonding may be present, it isincidental to the retention of the block copolymer in the polymericarticle. Whatever incidental covalent bonding may be present, it wouldnot by itself be sufficient to maintain the association of thenon-reactive block copolymers with or in the polymer matrix. Instead,the vastly predominating effect keeping the block copolymers associatedwith the polymeric article is entrapment of at least a portion of thehydrophobic segment. The hydrophobic segment is “entrapped”, accordingto this specification, when it is physically retained within or anchoredto the polymer matrix. This is done via entanglement of the hydrophobicsegment within the polymer matrix, van der Waals forces, dipole-dipoleinteractions, electrostatic attraction, hydrogen bonding andcombinations of these effects. In one embodiment, non-reactivecomponents are free from free radical reactive groups.

As used herein “segment” means a residue which has a structurecomprising repeating units.

The present invention provides a block copolymer formed from thereaction of at least one hydrophilic monomer and a macro initiator witha hydrophobic segment having a molecular weight between about 300 andabout 1800. If the molecular weight of the hydrophobic segment has amolecular weight distribution, the molecular weight is weight-averagemolecular weight.

The macro initiator may be obtained by reacting an azo-type initiatorwith a compound having the desired hydrophobic segment.

Azo-type initiators are known in the art and include aliphatic azocontaining initiators, including one or more of the following compounds:4,4′-azobis(4-cyanovalearic acid) and its derivatives,2,2′-azobis[N-(2-carboxyethyl)-2-methylpropionamidine]hydrate,2,2′-azobis{2-methyl-N-[2-(1-carboxybutyl)]propionamide}, and2,2′-azobis[2-methyl-N-(2-carboxyethyl)propionamide] and the like. Inone embodiment the azo-type initiator is 4,4′-azobis(4-cyanovalearicacid).

Hydrophobic segments of the present invention are those which do notyield a clear single phase when mixed with water at 2000 ppm at 25° C.When making this measurement, each end of the hydrophobic segment may beindependently substituted with a hydrogen atom or an initiator residue.Examples of suitable hydrophobic segments are polysiloxanes, C₈-C₅₀alkylene or (poly)arylene groups, hydrophobic polymers formed frommonomers selected from the group consisting of C₁-C₂₀ alkyl or C₆-C₂₀aryl (meth)acrylate monomers such as methyl (meth)acrylate, ethyl(meth)acrylate, n-propyl (meth)acrylate, isopropyl (meth)acrylate,n-butyl (meth)acrylate, n-decyl (meth)acrylate, n-dodecyl(meth)acrylate, phenyl (meth)acrylate, and naphthyl (meth)acrylate; andsilicone (meth)acrylate monomers such as3-(meth)acryloxypropyltris(trimethylsiloxy)silane,pentamethyldisiloxanylmethyl (meth)acrylate,methyldi(trimethylsiloxy)(meth)acryloxymethylsilane,mono(meth)acryloxypropy terminated mono-n-butyl terminatedpolydimethylsiloxane, (2-methyl-)2-propenoic acid,2-hydroxy-3-[3-[1,3,3,3-tetramethyl-1-[trimethylsilyl)oxy]disiloxanyl]propoxy]propyl ester, and9-n-butyl-1-[3-(3-(meth)acryloyloxy-2-hydroxypropoxy)propyl]-1,1,3,3,5,5,7,7,9,9-decamethylpentasiloxane;and vinyl or allyl silicone monomers such as3-[tris(trimethylsiloxy)silyl] propyl allyl carbamate,3-[tris(trimethylsiloxy)silyl]propyl vinyl carbamate,trimethylsilylethyl vinyl carbonate, trimethylsilylmethyl vinylcarbonate; and aromatic vinyl monomers such as styrene, andvinylpyridine; and combinations thereof. In one embodiment thehydrophobic segment of the block copolymer is a polysiloxane segment.The polysiloxane segment may comprise C₁-C₄ polyalkyl and polyarylsubstituted siloxane repeating units. Examples of suitable polysiloxanerepeating units include polydimethylsiloxane, polydiethylsiloxane,polydiphenylsiloxanes and copolymers thereof. In one embodiment thepolysiloxane segment is terminated on one end with an alkyl group, andin another embodiment a C₁₋₄ alkyl and in another methyl or n-butyl.

The hydrophobic segment of the block copolymer of the present inventionhas affinity towards polymeric articles formed from hydrophobiccomponents, such as, but not limited to silicone containing articles,such as, in one embodiment, silicone elastomer lenses and siliconehydrogel contact lenses.

The present invention further relates to a wetting agent for polymericarticles comprising at least partially hydrophobic polymers, such assilicone elastomer, silicone hydrogel and PMMA contact lenses. The blockcopolymers formed from the macroinitiators of the present invention may,in one embodiment be incorporated into packaging solutions, storagesolutions and multipurpose solutions containing the block copolymersformed via the present invention. These solutions can provide improvedwettability to the polymeric article without performing a surfacetreatment.

In one embodiment, the hydrophobic segment-containing macroinitiatorscomprise one or two hydrophobic segments, each having a molecular weightof about 300 to about 1800. In another embodiment, the hydrophobicsegment-containing macroinitiators comprise two hydrophobic segmentsbecause block copolymers only are obtained from the macroinitiators,while a mixture of block copolymers and hydrophilic polymers areobtained from macroinitiators comprising one hydrophobic segment. Thehydrophobic segment may be formed from monomers which will associate, ona “like prefers like” basis with at least a part of the hydrophobicnetwork of a polymeric article. For example, in one embodiment where thearticle is an ophthalmic device such as a PMMA, siloxane elastomer orsilicone hydrogel contact lens, or a silicone elastomer punctal plug,the hydrophobic segment is a segment comprising polysiloxane.

The hydrophobic-containing macroinitiator may be formed by reacting areactive linear polysiloxane having a functional group such as ahydroxyl group, amino group, thiol group or the like on at least oneterminus with an azo-type initiator having a carboxy group.

The reactive linear polysiloxane may be selected from compounds of theformula:

Wherein R¹¹ is selected from substituted and unsubstituted C₁₋₂₄ alkyl;in some embodiments substituted and unsubstituted C₁₋₁₀ alkyl and inother embodiments unsubstituted C₁₋₄ alkyl, and in other embodimentsmethyl or n-butyl;

R¹²-R¹⁵ are independently selected from C₁-C₄ alkyl and C₆₋₁₀ aryl;

r is 5-60, 6-50, 6-20, 6-15 and in some embodiments 6-12, and R¹⁷, R¹⁸and R¹⁹ are independently selected from H, unsubstituted C₁₋₄ alkyl,C₁₋₄ alkyl substituted with hydroxyl, amino and the like andcombinations thereof, with the proviso that at least one of R¹⁷, R¹⁸ andR¹⁹ is a hydrogen atom or comprise a hydroxyl group, amino group orthiol group.

The molecular weight of the reactive linear polysiloxane is betweenabout 300 to about 1800, and in some embodiments between about 400 toabout 1500, about 500 to about 1500, and between about 800 to about1200.

Specific examples of reactive linear polysiloxanes include

Wherein m is 0 to 3, and n is r+1 and r is as defined above.

The reactive linear polysiloxane is reacted with an azo-type initiatorhaving a carboxy group or a vinyl group. Suitable azo-type initiatorsinclude 4,4′-azobis(4-cyanovalearic acid) and its derivatives,2,2′-azobis[N-(2-carboxyethyl)-2-methylpropionamidine]hydrate,2,2′-azobis{2-methyl-N-[2-(1-carboxybutyl)]propionamide}, and2,2′-azobis[2-methyl-N-(2-carboxyethyl)propionamide] and the like. Inone embodiment the azo-type initiator is 4,4′-azobis(4-cyanovalearicacid).

Generally it is desirable to control the ratio of reactive linearpolysiloxane to azo-type initiator in the reaction. If thesiloxane/initiator molar ratio is too high, siloxane raw material willremain after reaction, and purifying will be difficult, but if the ratiois too low (too much initiator), the yield will be reduced. Thereforeratios of 1 to 2.4, 1.3 to 2.0 and in some embodiments 1.4 to 1.9 aredesirable.

The azo-type initiator and reactive linear polysiloxane are reacted viaa condensation reaction or a hydrosilylation reaction at a sufficientlylow temperature that the azo type initiator does not generate radicals.If the reaction temperature is too high, radicals will be generated fromthe azo type initiator, but if the temperature is too low, a long timewill be required until the reaction is complete. Therefore the reactiontemperature is preferably from −20° C. to 50° C., more preferably from0° C. to 40° C., and most preferably from 10° C. to 35° C.

A condensation agent may also be included. Examples of condensationagents include dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide(DIPC), and N-ethyl-N′-3-dimethyl aminopropyl carbodiimide (EDC=WSCI),as well as hydrochloride salts (WSCI.HCl). A combination of DCC or WSCIand N-hydroxy succinimide (HONSu), 1-hydroxy benzotriazole (HOBt), or3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOBt) and the like canalso be used. If the amount used is too low, raw material will remainand purifying will be difficult, but if the amount is too high, thecondensation agent will remain and purifying will be difficult.Therefore, the molar ratio added is preferably 1.8 to 4.0 times theamount of azo type initiator having a carboxyl group, and the molarratio is more preferably 2.0 to 3.0 times, and most preferably 2.1 to2.7 times.

A catalyst can be added during the macro initiator synthesis reaction ofthe present invention in order to enhance reactivity. Suitable catalystsinclude nucleophilic catalysts such as, 4-dimethyl amino pyridine andthe like. If the amount used is too low, much time will be required forthe reaction, but if the amount is too high, removing the catalyst afterthe reaction will be difficult. Therefore molar ratios of catalyst toinitiator of about 0.01 to about 4.0, about 0.05 to about 3.0 aredesirable. In some embodiments, in order to prevent raw material fromremaining, a molar ratio of catalyst to initiator about 1.0 to about 2.7are preferred.

In one embodiment, the hydrophobic segment containing macroinitiators ofthe present invention have the formula:

wherein in (a0) and (a1), R¹ is one type of group selected from an alkylgroup or an alkoxy group;

R² is one type of group selected from (CH₂)_(n) and(CH₂)_(m)—O(CH₂)_(n);

m and n are independent, ranging from 1 to 16, more preferably from 2 to10, most preferably from 2 to 5;

a is from 4 to 19, more preferably from 6 to 17, and most preferablyfrom 8 to 15;

b is from 1 to 6, more preferably from 2 to 4; and

X is one type of group selected from O, NH, and S, more preferably O,and NH from the viewpoint of high reactivity, and most preferably O fromthe viewpoint of less byproduct.

The hydrophobic segment containing macroinitiators of the presentinvention are reacted with at least one hydrophilic monomer to form theblock copolymers of the present invention. In one embodiment thehydrophilic segment may be formed from known hydrophilic monomers.Hydrophilic monomers are those which yield a clear single phase whenmixed with water at 25° C. at a concentration of 10 wt %. Examples ofhydrophilic monomers include vinyl amides, vinylimides, vinyl lactams,hydrophilic (meth)acrylates, (meth)acrylamides, styrenics, vinyl ethers,vinyl carbonates, vinyl carbamates, vinyl ureas and mixtures thereof.

Examples of suitable hydrophilic monomers include N-vinyl pyrrolidone,N-vinyl-2-piperidone, N-vinyl-2-caprolactam,N-vinyl-3-methyl-2-caprolactam, N-vinyl-3-methyl-2-piperidone,N-vinyl-4-methyl-2-piperidone, N-vinyl-4-methyl-2-caprolactam,N-vinyl-3-ethyl-2-pyrrolidone, N-vinyl-4,5-dimethyl-2-pyrrolidone,vinylimidazole, N—N-dimethylacrylamide, acrylamide,N,N-bis(2-hydroxyethyl)acrylamide, acrylonitrile, N-isopropylacrylamide, vinyl acetate, (meth)acrylic acid, polyethylene glycol(meth)acrylates, 2-ethyl oxazoline, N-(2-hydroxypropyl)(meth)acrylamide, N-(2-hydroxyethyl) (meth)acrylamide,2-methacryloyloxyethyl phosphorylcholine,3-(dimethyl(4-vinylbenzyl)ammonio)propane-1-sulfonate (DMVBAPS),3-((3-acrylamidopropyl)dimethylammonio)propane-1-sulfonate (AMPDAPS),3-((3-methacrylamidopropyl)dimethylammonio)propane-1-sulfonate(MAMPDAPS),3-((3-(acryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (APDAPS),3-((3-methacryloyloxy)propyl)dimethylammonio)propane-1-sulfonate(MAPDAPS), N-vinyl-N-methylacetamide, N-vinylacetamide,N-vinyl-N-methylpropionamide, N-vinyl-N-methyl-2-methylpropionamide,N-vinyl-2-methylpropionamide, N-vinyl-N,N′-dimethylurea, and the like,and mixtures thereof. In one embodiment the hydrophilic monomercomprises N-vinyl pyrrolidone, N-vinyl-N-methylacetamide,2-methacryloyloxyethyl phosphorylcholine, (meth)acrylic acid, N,Ndimethylacrylamide and the like and mixtures thereof. In someembodiments the hydrophilic segment may also comprise charged monomersincluding but not limited to methacrylic acid, acrylic acid,3-acrylamidopropionic acid, 4-acrylamidobutanoic acid,5-acrylamidopentanoic acid, 3-acrylamido-3-methylbutanoic acid (AMBA),N-vinyloxycarbonyl-α-alanine, N-vinyloxycarbonyl-β-alanine (VINAL),2-vinyl-4,4-dimethyl-2-oxazolin-5-one (VDMO), reactive sulfonate salts,including, sodium-2-(acrylamido)-2-methylpropane sulphonate (AMPS),3-sulphopropyl (meth)acrylate potassium salt, 3-sulphopropyl(meth)acrylate sodium salt, bis 3-sulphopropyl itaconate di sodium, bis3-sulphopropyl itaconate di potassium, vinyl sulphonate sodium salt,vinyl sulphonate salt, styrene sulfonate, sulfoethyl methacrylate,combinations thereof and the like. In embodiments where the hydrophilicsegment comprises at least one charged hydrophilic monomer it may bedesirable to include non-charged hydrophilic monomers as comonomers.

In another embodiment the hydrophilic segment is made from a hydrophilicpolymer selected from a group consisting of poly-N-vinyl-2-pyrrolidone,poly-N-vinyl-2-piperidone, poly-N-vinyl-2-caprolactam,poly-N-vinyl-3-methyl-2-caprolactam, poly-N-vinyl-3-methyl-2-piperidone,poly-N-vinyl-4-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-caprolactam,poly-N-vinyl-3-ethyl-2-pyrrolidone,poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinyl imidazole,poly-N—N-dimethyl acrylamide, poly-N-vinyl-N-methyl acetamide, polyvinylalcohol, polyacrylic acid, polymethacrylic acid, and poly(hydroxyethylmethacrylate), as well as blends and copolymers thereof. In anotherembodiment the hydrophilic segment comprises a hydrophilic polymerselected from a group consisting of poly-N-vinyl-2-pyrrolidone,poly-N—N-dimethyl acrylamide, poly-N-vinyl-N-methyl acetamide, polyvinylalcohol, polyacrylic acid, polymethacrylic acid, and poly(hydroxyethylmethacrylate) and copolymers comprising them.

The hydrophilic monomer should be present in a concentration sufficientto achieve the desired degree of polymerization of the hydrophilicsegment. If the concentration of hydrophilic monomer is too high, highviscosity will occur during polymerization, and mixing will bedifficult, and in some cases impossible. Therefore a weight percentageof 10 to 60 weight % is preferable, and 15 to 50 weight % is mostpreferable.

If the monomer/initiator ratio is too low, gelling will readily occurduring polymerization, but if the ratio is too high, polymerization willnot start. Therefore, a ratio of 500 to 10,000 is preferable, 800 to7000 is more preferable, and 1500 to 5000 is most preferable.

The polymerization may be carried out neat or with a solvent. Suitablesolvents include ethers, esters, amides, aromatic and aliphatichydrocarbons, alcohols, ketone solvents, ester solvents, ether solvents,sulfoxide solvents, amide solvents, and glycol solvents andhalohydrocarbons. Among these, from the viewpoint of hard to inhibitradical polymerization, more preferable are water, and alcohol solvents,and most preferable are water and tertiary alcohol solvents. Exampleinclude t-amyl alcohol, diethyl ether, tetrahydrofuran, hexanes,methylene chloride, ethyl acetate, dimethyl formamide, water, methanol,ethanol, propanol, 2-propanol, butanol, tert-butanol,3-methyl-3-pentanol, 3,7-dimethyl-3-octanol, benzene, toluene, xylene,hexane, heptane, octane, decane, petroleum ether, kerosene, ligroin,paraffin, acetone, methyl ethyl ketone and methyl isobutyl ketone, ethylacetate, butyl acetate, methyl benzoate, dioctyl phthalate, ethyleneglycol diacetate, diethyl ether, tetrahydrofuran, dioxane, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycoldialkyl ether, diethylene glycol dialkyl ether, triethylene glycoldialkyl ether, tetraethylene glycol dialkyl ether, polyethylene glycoldialkyl ether, polyethylene glycol-polypropylene glycol block copolymer,and polyethylene glycol-polypropylene glycol random copolymer, andmixtures thereof and the like. Among these, from the viewpoint of hardto inhibit radical polymerization, more preferable are water,tert-butanol, tert-amyl alcohol, 3-methyl-3-pentanol and3,7-dimethyl-3-octanol. If a solvent is used it is present in amountsbetween about 40 to about 90% and in some embodiments between about 50and about 85%.

Any temperature where the selected initiator is active, and between thefreezing and boiling point of the reaction components (includingsolvent, if used) may be used. If the temperature is too high, thepolymer solution may also heat excessively and become difficult tocontrol or dangerous. Temperature ranges between the 10 hour half-lifetemperature of the polymerization initiator (hereinafter referred to asT) and T+50° C., and in some embodiments between T and T+30° C. aresuitable.

Suitable reaction times include up to about 72 hours and in someembodiments from about 1 to about 24 hours and in other embodiments fromabout 2 to about 10 hours.

The resulting block copolymer may purified via distillation, columnchromatography, precipitation, washing off impurities by solvent whichthe block copolymer is insoluble to, fractionation by GPC, or any othertraditional means of polymer isolation.

The block copolymer may be expressed by formula (b1) or (b2).

Formula:

(wherein in (b1) and (b2), R¹ is one type of group selected from analkyl group or an alkoxy group;

R² is one type of group selected from (CH₂)_(n) or (CH₂)_(m)—O(CH₂)_(n);

m and n are independent, ranging from 1 to 16, more preferably from 2 to10, most preferably from 2 to 5;

a is from 4 to 19, more preferably from 6 to 17, and most preferablyfrom 8 to 15;

b is from 1 to 6, more preferably from 2 to 4, c is from 1 to 10,000,more preferably from 100 to 8000, and most preferably from 1000 to 6000,

X is one type of group selected from O, NH, and S, more preferably O,and NH from the viewpoint of high reactivity, and most preferably O fromthe viewpoint of less byproduct; and

R³ and R⁴ represent groups made of monomers with hydrophilicity whereina monomer is expressed by general formula (n)).

The block copolymers of the present invention have average molecularweights from about 10,000 to about 3,000,000 more preferably from about50,000 to about 1,000,000, and most preferably from about 100,000 toabout 600,000. If the average molecular weight is too low, the blockcopolymers will not provide enough wettability. However, if the averagemolecular weight is too high, the viscosity of the block copolymersolution is too high. In another embodiment, the block copolymers of theinvention further comprising about 0.01 to about 5 weight % of at leastone hydrophobic segment and about 95 to about 99.99 weight % of ahydrophilic segment, more preferably approximately 0.05 to approximately3 weight % of a hydrophobic segment and approximately 97 toapproximately 99.95 weight % of a hydrophilic segment, and mostpreferably approximately 0.1 to approximately 1 weight % of ahydrophobic segment and approximately 99 to approximately 99.9 weight %of a hydrophilic segment.

In some embodiments the block copolymer contains approximately 0.01 toapproximately 5 weight % of a hydrophobic segment and approximately 95to approximately 99.9 weight % of a hydrophilic segment.

If the silicone (PDMS) block in the block copolymer is too large, eventhough the block copolymer overall is hydrophilic due to the degree ofpolymerization of the hydrophilic monomer, the overall solubility of theblock copolymer will be insufficient. However, if the silicone segmentis too small the block copolymer will not persistently associate withthe polymeric article and will not provide the desired benefit over theuseful life of the article.

The block copolymers of the present invention are non-reactive. Thepresent invention further relates to polymeric materials, and in someembodiments medical devices formed from polymeric materials have theblock copolymers of the present invention associated therewith.

Suitable medical devices include ophthalmic lenses, endoscopes,catheters, transfusion tubes, gas transport tubes, stents, sheaths,cuffs, tube connectors, access ports, drainage bags, blood circuits,wound covering material, implants and various types of medicinecarriers, but is particularly suitable for ophthalmic devices, includingcontact lenses, ophthalmic lenses, punctal plugs and artificial corneas.

Where the medical device is an ophthalmic device it may be a contactlens, corneal implant, punctal plug or the like. Suitable siliconehydrogel materials are known and may be used, including but not limitedto senofilcon, galyfilcon, lotrafilcon A and lotrafilcon B, balafilcon,comfilcon and the like. Almost any silicone hydrogel polymer can betreated using the hydrophilic polymers of the present invention,including but not limited to those disclosed in U.S. Pat. No. 6,637,929,WO03/022321, WO03/022322, U.S. Pat. No. 5,260,000, U.S. Pat. No.5,034,461, U.S. Pat. No. 6,867,245, WO2008/061992, U.S. Pat. No.5,760,100, U.S. Pat. No. 7,553,880.

The present invention further relates to optically clear, aqueoussolutions comprising at least one block copolymer of the presentinvention in an amount sufficient to reduce at least one of contactangle, lipid uptake or protein uptake. Suitable amounts include up toabout 5000 ppm, about 50 to about 3000 ppm and about 100 to about 2000ppm. The block copolymer may be incorporated into said polymeric articlein amounts from about 0.1 ppm to about 30% of the block copolymer morepreferably from about 1000 ppm to about 25%, and most preferably fromabout 1% to about 20%.

The hydrophilic polymers of the present invention may be non-covalentlyassociated with a variety of polymers including polysiloxanes, siliconehydrogels, polymethyl methacrylate, polyethylene, polypropylene,polycarbonate, polyethylene terapthalate, polytetrafluoroethylene, andmixtures thereof and the like. In this embodiment it is believed thatthe terminal polysiloxane associates with the substrate which compriseshydrophobic polymer components. In this embodiment the block copolymeris dissolved in a solvent which also swells the substrate. The polymersubstrate is contacted with the solution comprising the block copolymer.When the substrate is a silicone hydrogel article, such as a contactlens, suitable solvents include packing solution, storing solution andcleaning solutions. Using this embodiment as an example, the siliconehydrogel lens is placed in a packing solution comprising the blockcopolymer. The hydrophilic polymer is present in the solution in amountsbetween about 0.001 and about 10%, in some embodiments between about0.005 and about 2% and in other embodiments between about 0.01 and about0.5 weight %, based upon all components in the solution.

The packing solutions of the invention may be any water-based solutionthat is used for the storage of contact lenses. Typical solutionsinclude, without limitation, saline solutions, other buffered solutions,and deionized water. The preferred aqueous solution is saline solutioncontaining salts including, without limitation, sodium chloride, sodiumborate, sodium phosphate, sodium hydrogenphosphate, sodiumdihydrogenphosphate, or the corresponding potassium salts of the same.These ingredients are generally combined to form buffered solutions thatinclude an acid and its conjugate base, so that addition of acids andbases cause only a relatively small change in pH. The buffered solutionsmay additionally include 2-(N-morpholino)ethanesulfonic acid (MES),sodium hydroxide, 2,2-bis(hydroxymethyl)-2,2′,2″-nitrilotriethanol,N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid, citric acid,sodium citrate, sodium carbonate, sodium bicarbonate, acetic acid,sodium acetate, ethylenediamine tetraacetic acid and the like andcombinations thereof. Preferably, the solution is a borate buffered orphosphate buffered saline solution. The solutions may also include knownadditional components such as viscosity adjusting agents, antimicrobialagents, polyelectrolytes, stabilizers, chelants, antioxidants,combinations thereof and the like.

The substrate is contacted with the block copolymer under conditionssufficient to incorporate a lubricious and surface-wetting effectiveamount of the block copolymer. As used herein, a lubricious effectiveamount, is an amount necessary to impart a level of lubricity which maybe felt manually (such as by rubbing the device between one's fingers)or when the device is used. Additionally, as used herein, asurface-wetting effective amount is an amount necessary to impart alevel of increased wettability to the lens, as determined via knowncontact angle measurement techniques (i.e. sessile drop, captive bubble,or dynamic contact angle measurements). It has been found that in oneembodiment, where the device is a soft contact lens, amounts ofhydrophilic polymer as little as 50 ppm provide improved lens “feel” andlowered surface contact angles, as measured by sessile drop. Amounts ofblock copolymer greater than about 50 ppm, and more preferably amountsgreater than about 100 ppm, (measured via extraction in 2 ml of a 1:1DMF:deionized water solution, for 72 hours) add a more pronouncedimprovement in feel. Thus, in this embodiment, the block copolymer mayincluded in a solution in concentrations up to about 5000 ppm, in someembodiments between about 10 and 3000 ppm, and in some embodimentsbetween about 10 and about 2000 ppm. The packaged lens may be heattreated to increase the amount of hydrophilic polymer which permeatesand becomes entangled in the lens. Suitable heat treatments, include,but are not limited to conventional heat sterilization cycles, whichinclude temperatures of about 120° C. for times of about 20 minutes andmay be conducted in an autoclave. If heat sterilization is not used, thepackaged lens may be separately heat treated. Suitable temperatures forseparate heat treatment include at least about 40° C., and preferablybetween about 50° C. and the boiling point of the solution. Suitableheat treatment times include at least about 10 minutes. It will beappreciated that higher temperatures will require less treatment time.

In one embodiment, the polymeric article is formed from a reactivemixture comprising a silicone monomer comprising a hydroxyl group.

Treatment of the polymeric article with the block copolymer can beperformed on the entire polymer or can be performed only on a portion ofthe polymer such as only on the surface or a portion of the surface.

The present invention will be described in further detail below throughthe use of working examples, but the present invention is not limited tothese working examples.

Analytical Methods (1) GPC Measurement

GPC measurement was performed at the following conditions.

Equipment: Tosoh Corporation

Column: TSKgel SUPER HM_H, 2 columns (particle diameter; 5 μm, 6.0 mmID×15 cm)

Mobile phase: N-methyl pyrrolidone (10 mM LiBr)

Column temperature: 40° C.

Measurement time: 40 minutes

Injection quantity: 10 μL

Detector: RI detector

Flow rate: 0.2 mL/minute

Sample concentration: 0.4 weight %

Standard sample: polystyrene (molecular weight 500 to 1.09 million)

(2) Transmission Measurement

A packaging solution made by dissolving 2000 ppm of block copolymer wasplaced in a quartz cell, and a transmissivity was measured using a colorcomputer (model: SM7-CH) manufactured by Suga Test Instruments Co., Ltd.

(3) Contact Angle Measurement

Wettability of lenses was determined using a sessile drop techniquemeasured using KRUSS DSA-100™ instrument at room temperature and usingDI water as probe solution. The lenses to be tested (3-5/sample) wererinsed in DI water to remove carry over from packing solution. Each testlens was placed “bowl side down” on the convex surface of the lensholder, ensuring proper central syringe alignment and that the syringecorresponds to the assigned liquid. Blotting paper (dry Whatman #1filter paper on a glass sheet) is gently placed on the lens without anydownward pressure for 20 seconds. A 3 to 4 microliter of DI water dropwas formed on the syringe tip using DSA 100-Drop Shape Analysis softwareensuring the liquid drop was hanging away from the lens. The drop wasreleased smoothly on the lens surface by moving the needle down. Theneedle was withdrawn away immediately after dispensing the drop. Theliquid drop was allowed to equilibrate on the lens for 5 to 10 secondsand the contact angle was computed based on the contact angle measuredbetween the drop image and the lens surface.

(4) Lipid Uptake

A standard curve was set up for each lens type under investigation.Tagged cholesterol (cholesterol labeled with NBD([7-nitrobenz-2-oxa-1,3-diazol-4-yl], CH-NBD; Avanti, Alabaster, Ala.))was solubilized in a stock solution of 1 mg/mL lipid in methanol at 35°C. Aliquots were taken from this stock to make standard curves inphosphate-buffered saline (PBS) at pH 7.4 in a concentration range from0 to 100 micg/mL.

One milliliter of standard at each concentration was placed in the wellof a 24-well cell culture plate. 10 lenses of each type were placed inanother 24-well plate and soaked alongside the standard curve samples in1 mL of a concentration of 20 micg/ml of CH-NBD. Another set of lenses(5 lenses) were soaked in PBS without lipids to correct for anyautofluorescence produced by the lens itself. All concentrations weremade up in phosphate buffered saline (PBS) at pH 7.4. Standard curves,test plates (containing lenses soaked in CH-NBD) and control plates(containing lenses soaked in PBS) were all wrapped in aluminum foil tomaintain darkness and were incubated for 24 hours, with agitation at 35°C. After 24 hours the standard curve, test plates and control plateswere removed from the incubator. The standard curve plates wereimmediately read on a micro-plate fluorescence reader (Synergy HT)).

The lenses from the test and control plates were rinsed by dipping eachindividual lens 3 to 5 times in 3 consecutive vials containingapproximately 100 ml of PBS to ensure that only bound lipid would bedetermined without lipids carryover. The lenses were then placed in afresh 24-well plate containing 1 mL of PBS in each well and read on thefluorescence reader. After the test samples were read, the PBS wasremoved, and 1 mL of a fresh solution of CH-NBD were placed on thelenses in the same concentrations as previously mentioned and placedback in the incubator at 35° C., with rocking, until the next period.This procedure was repeated for 15 days until complete saturation oflipids on lenses. Only the lipid amount obtained at saturation wasreported.

Working Example 1

1.68 g (6 mmol) of 4,4′-azobis(4-cyanovalearic acid) and 1.83 g (15mmol) of 4-dimethyl amino pyridine, 3.0 g (15 mmol) of N,N-dicyclohexylcarbodiimide, and 40 mL of acetone were added to a 200 mL three mouthflask equipped with a calcium chloride tube under nitrogen gas flow.8.58 g (9 mmol) of polydimethylsiloxane having a hydroxyl group at oneend and expressed by the following formula (a2)

(manufactured by Chisso Corporation FM-0411, Mw 1000) was added by dropsto the solution and agitated for six hours at room temperature. Aprecipitated solid was filtered out, hexane was added to the filtrateobtained, and then the filtrate was washed two times with 0.5 N HCl, twotimes with saturated sodium bicarbonate aqueous solution, and one timewith saturated sodium chloride aqueous solution. The organic phase wasdried using sodium sulfate, filtered, and then concentrated to obtaincrude product. The crude product was purified using a silica gel column(silica gel 180 g, hexane/ethyl acetate=100/0→10/1 (v/v), 400 mL each),and 5.18 g of the target silicone macro initiator was obtained.

Working Example 2

1.40 g (5 mmol) of 4,4′-azobis(4-cyanovalearic acid), 9.1 g (9.1 mmol)of polydimethylsiloxane having an amino group at one end and expressedby the following formula (a3) (manufactured by Chisso Corporation,FM0311, Mw 1000), 0.67 g (5.5 mmol) of 4-dimethyl aminopyridine, and 50mL of acetone were added to a 200 mL three mouth flask equipped with acalcium chloride tube under nitrogen gas flow.

1.70 mL (11 mmol) of N,N-diisopropyl carbodiimide was added by drops tothis blended solution. After agitating for 6 hours at ambienttemperature, a precipitated solid was filtered out, hexane was added tothe filtrate obtained, and then the filtrate was washed two times with0.5 N HCl, two times with saturated sodium bicarbonate aqueous solution,and one time with saturated sodium chloride aqueous solution. Theorganic phase was dried using sodium sulfate, filtered, concentrated,and then the crude product was purified using a silica gel column(silica gel 180 g, hexane/ethyl acetate=10/1→3/1→2/1, 300 mL each), and1.89 g of the target silicone macro initiator was obtained.

Comparative Example 1

The silicone macro initiator wherein the molecular weight of thesilicone portion is 5000 was obtained by using the same method asWorking Example 1 except that the polydimethylsiloxane containing ahydroxyl group on one end (a2) was replaced a polydimethylsiloxane ofthe same structure, but having a higher molecular weight (manufacturedby Chisso Corporation, FM-0421, Mw 5000). The resulting siliconemacroinitiator was purified as described in Working Example 1.

Comparative Example 2

The silicone macro initiator wherein the molecular weight of thesilicone portion is 10,000 was obtained by the same method as WorkingExample 1 except that the polydimethylsiloxane containing a hydroxylgroup on one end (a2) was replaced a polydimethylsiloxane of the samestructure, but having a higher molecular weight (manufactured by ChissoCorporation, FM-0425, Mw 10,000), and then purifying.

Working Example 3

N-vinyl pyrrolidone (NVP, 29.56 g, 0.266 mol), the silicone macroinitiator expressed by the following formula (a4) obtained by workingexample 1 (Mw of silicone portion is 1000, 0.19 g, 0.0866 mmol), andt-amyl alcohol (TAA, 69.42 g) were added to a 200 mL three mouth flask,and then a three way cock, thermometer, and mechanical stirrer wereattached.

The inside of the three mouth flask was evacuated using a vacuum pumpand then substituted with argon, three times, and then the temperaturewas increased to 70° C. After confirming that the temperature hadstabilized and heat generation was not occurring, the temperature wasincreased to 75° C. and the sample was agitated for 6 hours.

After polymerization was complete, the temperature was cooled to roomtemperature, and then the sample was poured into n-hexane/ethanol=500mL/40 mL and allowed to sit. The supernatant fluid was removed bydecanting, and then the washing was performed 2 times usingn-hexane/ethanol=500 mL/20 mL. The solid fraction obtained was dried for16 hours at 40° C. in a vacuum dryer, and then liquid nitrogen wasadded, the sample was crushed using a spatula, and then transferred to abag with a zipper. Drying was performed for 3 hours at 40° C. using avacuum dryer to obtain a block copolymer. The molecular weight of theblock copolymer obtained was as shown in Table 1.

Working Examples 4 Through 10

Additional block copolymers were formed according to the procedure ofWorking Example 3, but with the components in the amounts indicated inTable 1. The molecular weight of the block copolymer obtained was asshown in Table 1.

Working Example 11

N-vinyl pyrrolidone (NVP, 31.12 g, 0.28 mol), the silicone macroinitiator expressed by the following formula (a5) obtained by WorkingExample 1 (Mw of silicone portion is 1000, 0.15 g, 0.07 mmol), andt-amyl alcohol (TAA, 72.96 g) were added to a 200 mL three mouth flask,and then a three way cock, thermometer, and mechanical stirrer wereattached.

The inside of the three mouth flask was evacuated using a vacuum pumpand then substituted with argon, three times, and then the temperaturewas increased to 70° C. After confirming that the temperature hadstabilized and heat generation was not occurring, the temperature wasincreased to 75° C. and the sample was agitated for 6 hours.

After polymerization was complete, the temperature was cooled to roomtemperature, and then the sample was poured into n-hexane/ethanol=600mL/20 mL and allowed to sit. The supernatant fluid was removed bydecanting, and then the washing was performed 2 times usingn-hexane/ethanol=500 mL/20 mL. The solid fraction obtained was dried for16 hours at 40° C. in a vacuum dryer, and then liquid nitrogen wasadded, the sample was crushed using a spatula, and then transferred to abag with a zipper. Drying was performed for 3 hours at 40° C. using avacuum dryer to obtain a block copolymer. The molecular weight of theblock copolymer obtained was as shown in Table 1.

Working Examples 12 Through 13

Additional block copolymers were formed according to the procedure ofWorking Example 11, but with the components in the amounts indicated inTable 1. The molecular weight of the block copolymer obtained was asshown in Table 1.

Comparative Example 3

Polymerization was performed by the same method as Working Example 3,except that the polymerization initiator was substituted with thesilicone macroinitiator of Comparative Example 1 (molecular weight (Mw)of the silicone portion 5000), and the amounts of the components usedwere as indicated in Table 1. The molecular weight of the blockcopolymer obtained was as shown in Table 1.

Comparative Example 4 and 5

Polymerization was performed by the same method as Working Example 3,except that the polymerization initiator was substituted with a siliconemacroinitiator of Comparative Example 2 (molecular weight (Mw) of thesilicone portion 10,000), and the amounts of the components used were asindicated in Table 1. The molecular weight of the block copolymerobtained was as shown in Table 1.

TABLE 1 macro-initiator Ex.# NVP (g) Ex# (g) TAA (g) Mn (kD) Mw (kD) 329.56 1 0.19 69.42 113.3 293.9 4 24.62 1 0.19 24.81 132.0 509.0 5 25.9 10.19 39.15 148.5 505.0 6 15.54 1 0.2 36.9 48.5 135.4 7 31.07 1 0.1 72.7378.4 189.2 8 5.18 1 0.1 29.92 42.7 93.8 9 19.45 1 0.15 45.73 88.7 251.610 31.10 1 0.15 72.92 70.9 198.1 11 31.12 2 0.15 72.96 80.0 228.8 1223.34 2 0.15 35.24 103.1 353.7 13 23.34 2 0.15 23.49 114.6 406.8 CE315.34 CE1 0.46 36.87 69.9 183.9 CE4 16.67 CE2 1.0 41.23 68.69 172.39 CE544.46 CE2 1.0 106.1 67.96 166.94

Working Example 14

Polymerization was performed by the same method as Working Example 3,except that NVP was substituted with N,N-dimethylacrylamide (DMA), andthe amounts of the components used were as indicated in Table 2. Themolecular weight of the block copolymer obtained was as shown in Table2.

Working Example 15 Through 16

Additional block copolymers were formed according to the procedure ofWorking Example 14, but with the components in the amounts indicated inTable 2. The molecular weight of the block copolymer obtained was asshown in Table 2.

TABLE 2 macro-initiator Ex.# DMA (g) Ex# (g) TAA (g) Mn (kD) Mw (kD) 1417.4 1 0.15 40.8 222.5 582.8 15 34.7 1 0.15 81.3 263.4 693.3 16 26.4 10.19 62.0 204.1 728.4

Working Example 17

The block copolymers obtained by Working Examples 3 through 8 and 11through 14, as well as comparative examples 3 through 5 were dissolvedat a concentration of 2000 ppm in packaging solutions. Thetransmissivity of the solutions obtained was measured and are shown inTable 3.

TABLE 3 Silicone portion Block copolymer Transmissivity Ex# Mw Mn (kD)Mw (kD) (%) Transparency 3 1000 113.3 293.9 97.37 Transparent 4 1000132.0 509.0 96.97 Transparent 5 1000 148.5 505.0 96.38 Transparent 61000 48.5 135.4 97.76 Transparent 7 1000 78.4 189.2 96.74 Transparent 81000 42.7 93.8 93.65 Transparent 11 1000 80.0 228.8 98.57 Transparent 121000 103.1 353.7 98.38 Transparent 13 1000 114.6 406.8 97.30 Transparent14 1000 204.1 728.4 97.37 Transparent CE3 5000 69.9 183.9 91.39 Whitecloudy CE4 10,000 68.69 172.39 78.63 White cloudy CE5 10,000 67.96166.94 89.38 White cloudy

As shown in Table 3, the copolymers of Examples 3 through 8 and 11-14all formed transparent solutions, even at 2000 ppm. When the molecularweight of the siloxane segment was above about 5000 (ComparativeExamples 3 through 5) the transmissivity of the 2000 ppm solution wasreduced and a clear solution could not be obtained.

Working Example 18

ACUVUE OASYS with Hydraclear Plus contact lenses (senofilcon A) wereimmersed in packaging solutions obtained by dissolving 2000 ppm of theblock copolymers obtained in Working Examples 3, 9, and 10, and thenimmersing for 24 hours in a packaging solution that did not contain theblock copolymer. The samples were removed and the contact angle wasmeasured. The results are shown in Table 4. A lipid uptake test was alsoperformed, and the results are shown in Table 4. All of the lenses werefound to have reduced lipid uptake compared to the lenses which were notsoaked in the block copolymers.

TABLE 4 Contact lipid uptake Copolymer Ex# angle (°) (μg/lens) Notreatment 53 28.2 3 38 14.4 9 69 14.8 10  57 15.1

1-13. (canceled)
 14. The medical device according to claim 19, wherein aweight-average molecular weight of the block copolymer is fromapproximately 10,000 to approximately 3,000,000.
 15. The medical deviceaccording to claim 19, wherein the block copolymer containsapproximately 0.01 to approximately 5 weight % of a hydrophobic segmentand approximately 95 to approximately 99.9 weight % of a hydrophilicsegment. 16-18. (canceled)
 19. A medical device comprising a siliconehydrogel and a block copolymer expressed by formula (b1) or (b2):

wherein in (b1), R¹ is selected from the group consisting of an alkylgroup or an alkoxy group; R² is selected from the group consisting(CH₂)_(n) and (CH₂)_(m)—O(CH₂)_(n); m and n are independent, rangingfrom 1 to 16; a is from 4 to 19; b is from 1 to 6, c is from 1 to10,000, X is selected from the group consisting O, NH, and S; and R³ andR⁴ represent hydrophilic groups from hydrophilic monomers expressed bygeneral formula (n)


20. The medical device according to claim 19, comprising approximately0.1 ppm to approximately 30% of the block copolymer.
 21. The medicaldevice according to any one of claims 19 through 20, wherein thesilicone hydrogel is formed from a reactive mixture comprising at leastone hydrophilic monomer selected from the group consisting ofN,N-dimethyl acrylamide (DMA), 2-hydroxyethyl acrylate, glycerolmethacrylate, 2-hydroxyethyl methacrylate amide, polyethylene glycolmono methacrylate, methacrylic acid, acrylic acid, N-vinyl pyrrolidone,N-vinyl-N-methyl acetamide, N-vinyl-N-ethyl acetamide, N-vinyl-N-ethylform amide, N-vinyl formamide, N-2-hydroxyethyl vinyl carbamate,N-carboxy-beta-alanine N-vinylester, reactive polyethylene polyol,hydrophilic vinyl carbonate, vinyl carbamate monomer, hydrophilicoxazolone monomer, hydrophilic oxazoline monomer, and combinationsthereof.
 22. The medical device according to any one of claims 19through 21, wherein the silicone hydrogel is formed from a reactivemixture comprising at least one silicone monomer comprising at least onehydroxyl group.
 23. The medical device according to claim 22, whereinsaid reactive mixture comprises approximately 5 to approximately 95weight % silicone containing components.
 24. The medical deviceaccording to claim 19 wherein said medical device is an ophthalmicdevice.
 25. The ophthalmic device according to claim 24 wherein saidophthalmic device is a contact lens.
 26. The medical device of claim 19wherein the block copolymer is a copolymer of Formula (b1).
 27. Themedical device of claim 19 or 24-26 wherein said hydrophilic monomer ofFormula n is selected from the group consisting of vinyl amides,vinylimides, vinyl lactams, hydrophilic (meth)acrylates,(meth)acrylamides, styrenics, vinyl ethers, vinyl carbonates, vinylcarbamates, vinyl ureas and mixtures thereof.
 28. The medical device ofclaim 19 or 24-26 wherein said hydrophilic monomer reacted to form saidblock copolymer is selected from the group consisting of N-vinylpyrrolidone, N-vinyl-2-piperidone, N-vinyl-2-caprolactam,N-vinyl-3-methyl-2-caprolactam, N-vinyl-3-methyl-2-piperidone,N-vinyl-4-methyl-2-piperidone, N-vinyl-4-methyl-2-caprolactam,N-vinyl-3-ethyl-2-pyrrolidone, N-vinyl-4,5-dimethyl-2-pyrrolidone,vinylimidazole, N—N-dimethylacrylamide, acrylamide,N,N-bis(2-hydroxyethyl)acrylamide, acrylonitrile, N-isopropylacrylamide, vinyl acetate, (meth)acrylic acid, polyethylene glycol(meth)acrylates, 2-ethyl oxazoline, N-(2-hydroxypropyl)(meth)acrylamide, N-(2-hydroxyethyl) (meth)acrylamide,2-methacryloyloxyethyl phosphorylcholine,3-(dimethyl(4-vinylbenzyl)ammonio)propane-1-sulfonate (DMVBAPS),3-((3-acrylamidopropyl)dimethylammonio)propane-1-sulfonate (AMPDAPS),3-((3-methacrylamidopropyl)dimethylammonio)propane-1-sulfonate(MAMPDAPS),3-((3-(acryloyloxy)propyl)dimethylammonio)propane-1-sulfonate (APDAPS),3-((3-methacryloyloxy)propyl)dimethylammonio)propane-1-sulfonate(MAPDAPS), N-vinyl-N-methylacetamide, N-vinylacetamide,N-vinyl-N-methylpropionamide, N-vinyl-N-methyl-2-methylpropionamide,N-vinyl-2-methylpropionamide, N-vinyl-N,N′-dimethylurea, and mixturesthereof.
 29. The medical device of claim 19 or 24-26 wherein saidhydrophilic monomer comprises at least one monomer selected from thegroup consisting of N-vinyl pyrrolidone, N-vinyl-N-methylacetamide,2-methacryloyloxyethyl phosphorylcholine, (meth)acrylic acid, N,Ndimethylacrylamide and mixtures thereof.
 30. The medical device of claim19 or 24-26 wherein R¹ is methyl or butyl.